5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivatives of salts thereof

ABSTRACT

5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivatives represented by the following general formula [I] ##STR1## wherein R 1 , R 2 , R 3  and R 4  are either the same or different and mean individually a hydrogen atom or lower alkyl group, Y denotes a specific phenyl-containing substituted amino group, and their salts. These compounds have excellent immuno-modulating activities.

This is a continuation of application Ser. No. 853,204, filed Apr. 17, 1986, now abandoned.

BACKGROUND OF THE INVENTION

(1) Field of the Invention:

This invention relates to novel 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivatives, and more specifically to 5,6-dihydroimidazo[2,1-b]-thiazole-2-carboxamide derivatives having excellent immuno-modulating activities.

(2) Description of the Prior Art:

A number of compounds having the imidazothiazole skeleton have heretofore been synthesized. For example, an imidazo[2,1-b]thiazole derivative (levamisole) represented by the following formula: ##STR2## has been reported to have some immuno-modulating activities (German Offenlegungsschrift No. 23 40 632).

It has also been reported that certain anti-inflammatory activities are exhibited by imidazo[2,1-b]thiazole derivatives represented by the following formula: ##STR3## wherein R₁₀ means a C₁ -C₃ -alkylsulfonyl or ##STR4## group, R₁₄ and R₁₅ being independently a hydrogen atom or a monofluorophenyl, trifluoromethylphenyl or trimethylphenyl group with a proviso that when either one of R₁₄ and R₁₅ is a hydrogen atom the other one is other than a hydrogen atom or being coupled to each other together with the associated nitrogen atom to form a 1-(2,3-dimethyl)pyrrolidinyl group, R₁₁ denotes a C₁ -C₃ -alkyl or phenyl group, and R₁₂ and R₁₃ stand independently for a hydrogen atom or a C₁ -C₄ -alkyl group [U.S. Pat. No. 4,224,334; J. Med. Chem. 24, 604-609 (1981)]; and by 5,6-dihydroimidazo[2,1-b]thiazole derivatives represented by the following formula: ##STR5## wherein R₁₆ means a substituted or unsubstituted phenyl or naphthalyl group (Japanese Patent Laid-Open No. 169490/1982).

SUMMARY OF THE INVENTION

An object of this invention is to provide certain imidazo[2,1-b]thiazole derivatives having excellent immuno-modulating activities.

With the foregoing in view, the present inventors synthesized a variety of imidazo[2,1-b]-thiazole derivatives and their physiological activities were investigated. As a result, it has been found that novel 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivatives having certain specific substituents and represented by the above general formula (I) have excellent immuno-modulating activities, leading to completion of this invention.

In one aspect of this invention, there is thus provided a 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative represented by the following general formula [I] ##STR6## wherein R₁, R₂, R₃ and R₄ are either the same or different and mean individually a hydrogen atom or lower alkyl group, Y denotes a group of the following formula: ##STR7## wherein R₅ means a lower alkyl group, X denotes a hydrogen or halogen atom or a trifluoromethyl, lower alkyl, lower alkoxy or nitro group, n stands for an integer of 0-5, and when n is greater than 1, Xs are either the same or different; ##STR8## wherein A means a lower alkylene group which may be branched, R₆ denotes a hydrogen atom or a lower alkyl or cycloalkyl group, and X and n have the same meaning as defined above; ##STR9## wherein R₇ means a hydrogen, chlorine, bromine or iodine atom or a lower alkyl, lower alkoxy or nitro group; or ##STR10## wherein R₈ means a halogen atom or a lower alkoxy or trifluoromethyl group and R₉ denotes a halogen atom or a hydroxyl, lower alkoxy or trifluoromethyl group), with a proviso that at least one of R₁, R₂, R₃ and R₄ is a methyl group when the group Y is ##STR11## or a salt thereof.

As salts of the 5,6-dihydroimidazo[2,1-b]-thiazole-2-carboxamide derivatives in the present invention, may be mentioned their pharmacologically acceptable salts, for example, their inorganic and organic acid salts such as hydrochlorides, sulfates, carbonates, nitrates, hydrobromides, phosphates, sulfonates, acetates, oxalates, tartrates, citrates, malates, glutamates, aspartates, etc. The compounds (I) of this invention and their salts may contain water of crystallization. Their hydrates are all embraced within the scope of this invention.

The compounds (I) of this invention and their salts have excellent immuno-modulating activities and can hence be used, as preventive and therapeutic medicines for immunological disease, for the treatment and prevention of autoimmune diseases such as chronic rheumatoid arthritis, systemic lupus erythematodes, collagen disease, chronic nephritis and autoimmunohemolytic anemia, delayed-type and immediate-type allergic diseases, malignant tumors and serious infectious diseases by way of example.

The above and other objects, features and advantages of this invention will become apparent from the following description and the appended claims.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The compounds (I) of this invention may be roughly divided into the following three groups (Ia)-(Ic): ##STR12## wherein Z means a group of the following formula: ##STR13## wherein R₇ means a hydrogen, chlorine, bromine or iodine atom or a lower alkyl, lower alkoxy or nitro group; or ##STR14## wherein R₈ means a halogen atom or a lower alkoxy or trifluoromethyl group and R₉ denotes a halogen atom or a hydroxyl, lower alkoxy or trifluoromethyl group; and and R₁ -R₆, A, X and n have the same meaning as defined above.

The term "lower" as used herein such as "lower alkylene", "lower alkoxy" and the like means 1-5 carbon atoms.

Among the compounds (Ia), those represented by the following formula (Ia-1) are preferred: ##STR15## wherein m stands for an integer of 1-3, and R₁, R₃, R₄, R₆, X and n have the same meaning as defined above.

Of the compounds (Ia-1), particularly-preferred compounds are those having the formula (Ia-1) in which R₁, R₃, R₄ and R₆ mean individually a hydrogen atom or methyl group and X denotes a halogen atom or trifluoromethyl group.

Among the compounds (Ia-1), still preferred compounds are represented by the following formulae respectively. ##STR16## wherein R₁₉ means a hydrogen atom or alkyl group having 1-3 carbon atoms, m stands for an integer of 1-3, and X and n have the same meaning as defined above.

Among the compounds (Ib), those represented by he following formula (Ib-1) are preferred: ##STR17## wherein R₁₇ and R₁₈ may be either the same or different and mean individually a hydrogen, chlorine or iodine atom or trifluoromethyl group, with a proviso that R₁₈ is other than a trifluoromethyl group when R₁₇ is a hydrogen atom, and R₁ and R₃ have the same meaning as defined above. Of these, those represented by the formula (Ib-1) in which R₁ and R₃ are individually a hydrogen atom or methyl group are especially preferred.

Among the compounds (Ic), those represented by the following formula (Ic-1) are preferred: ##STR18## wherein R₃, R₄, R₅, X and n have the same meaning as defined above. Of these, particularly-preferred compounds are those represented by the formula (Ic-1) in which R₃ and R₄ are individually a hydrogen atom or methyl group, R₅ denotes a methyl or ethyl group, and X stands for a halogen atom or trifluoromethyl group.

The compounds (I) of this invention can each be prepared, for example, by reacting an imidazolidine-2-thione represented by the following formula (III) with an amid represented by the following formula (II) in accordance with the following reaction formula: ##STR19## wherein R₁, R₂, R₃, R₄ and Y have the same meaning as defined above.

It is preferable to conduct the above reaction in a suitable inert solvent. As an illustrative solvent useful in the above reaction, may be mentioned benzene, toluene, xylene, acetone, methyl ethyl ketone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, ethyl ether, tetrahydrofuran, dioxane, chloroform, water or the like.

The reaction temperature may be -5° C.-+100° C. or preferably +20° C.-+80° C. By proceeding with the reaction for 1-6 hours, the compound of this invention can be obtained with high yield and high purity.

In order to obtain the corresponding compound of the general formula (I) in its free form from the thus-obtained hydrochloride, it is necessary to treat the hydrochloride with a base, for example, an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate or ammonia or an organic base such as pyridine or triethylamine. In order to derive other salts, it is required to treat the free compound with corresponding acids, for example, sulfuric acid, carbonic acid, nitric acid, hydrobromic acid, phosphoric acid, sulfonic acid, acetic acid, oxalic acid, tartaric acid, citric acid, malic acid, glutamic acid, aspartic acid and/or the like.

The compound of the formula (II), which is employed as a raw material in the above process, can be prepare, for example, in accordance with the following reaction scheme, namely, by reacting an amine (V) with a diketene (IV) to obtain a compound (VI) and then chlorinating the compound (VI) with sulfuryl chloride [Chemical Abstracts, 19, 43 (1925)], N-chlorosuccinimide or the like. ##STR20## wherein Y has the same meaning as defined above.

The other raw material (III) can be prepared, for example, in the following manner base on the process described in Org. Synth. Coll. 3, 394: ##STR21##

When the group represented by Y is ##STR22## in the compounds (I) of this invention obtained in the above manner, the following specific groups may be mentioned as preferred examples of these groups: ##STR23##

When Y stands for any one of the above exemplified groups, at least one of R₁, R₂, R₃ and R₄ means a methyl group. The methyl group is substituted to the 5- or 6-position of the imidazothiazole skeleton. The 6-substituted compound is preferred.

[Effects]

Pharmacological effects of the compounds (I) of this invention and their salts will next be described

Test 1

Effect on anti-SRBC PFC response in vitro:

In an RPMI-1640 culture medium containing 10% of fetal calf serum (FCS), 1×10⁷ spleen cells of BALB/c mouse were cultured together with sheep erythrocytes (1×10⁶) and a sample compound (0.2 or 1 μg/ml) for 5 days in a CO₂ incubator (37° C.) in accordance with the method reported by Mischell, R. I. et al. in J. Exp. Med. 126, 423 (1967) (with some modifications). The number of resultant plaque forming cells was counted by the method proposed by Jerne and Nordin [Science 140, 405 (1963)]. Results are shown in Table 1-A - Table 1-C.

                                      TABLE 1-A                                    __________________________________________________________________________      ##STR24##                             (Ia)                                    Sample                         Immune response                                 compound                       potentiation activities                         (1 μg/ml)                                                                          R.sub.1                                                                           R.sub.2                                                                           R.sub.3                                                                            R.sub.4                                                                            R.sub.5                                                                            X.sub.n                                                                              (Control = 100%)                                __________________________________________________________________________     Comp'd 1                                                                              H  H  H   H   CH.sub.3                                                                           3,4-Cl.sub.2                                                                         377                                             Comp'd 30                                                                             H  H  CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           3-CF.sub.3                                                                           271                                             Comp'd 31                                                                             H  H  CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           3,4-Cl.sub.2                                                                         201                                             Comp'd 32                                                                             H  H  CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           3,5-(CF.sub.3).sub.2                                                                 199                                             Comp'd 3                                                                              H  H  CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           4-CF.sub.3                                                                           203                                             Comp'd 2                                                                              H  H  CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           3,5-Cl.sub.2                                                                         293                                             Comp'd 4                                                                              H  H  CH.sub.3                                                                           CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    3,4-Cl.sub.3                                                                         177                                             __________________________________________________________________________

                  TABLE 1-B                                                        ______________________________________                                          ##STR25##                    (Ib)                                                                   Immune response                                                                potentiation activ-                                                            ities (Control =                                                               100%)                                                    Sample                                0.2    1                                 compound                                                                               R.sub.1                                                                               R.sub.3                                                                               R.sub.4                                                                             R.sub.6                                                                             X.sub.n                                                                              μg/ml                                                                              μg/ml                          ______________________________________                                         Comp'd 45                                                                              H      H      H    H    4-Cl  252    302                               Comp'd 55                                                                              H      H      H    H    2,4-Cl.sub.2                                                                         183    --                                Comp'd 56                                                                              H      H      H    H    3,4-Cl.sub.2                                                                         239    --                                Comp'd 60                                                                              H      H      H    H    3,5-Cl.sub.2                                                                         --     190                               Comp'd 51                                                                              H      H      H    CH.sub.3                                                                            2,4-Cl.sub.2                                                                         --     267                               Comp'd 48                                                                              H      H      H    CH.sub.3                                                                            3,4-Cl.sub.2                                                                         341    --                                Comp' d 66                                                                             H      H      H    CH.sub.3                                                                            3-Cl  173    --                                Comp'd 88                                                                              H      CH.sub.3                                                                              CH.sub.3                                                                            H    3-Cl  --     212                               Comp'd 89                                                                              H      CH.sub.3                                                                              CH.sub.3                                                                            H    4-Cl  --     168                               Comp'd 91                                                                              H      CH.sub.3                                                                              CH.sub.3                                                                            H    3,4-Cl.sub.2                                                                         220    --                                Comp'd 92                                                                              H      CH.sub.3                                                                              CH.sub.3                                                                            H    3-CF.sub.3                                                                           361    638                               Comp'd 94                                                                              H      CH.sub.3                                                                              CH.sub.3                                                                            CH.sub.3                                                                            3-Cl  --     181                               Comp'd 95                                                                              H      CH.sub.3                                                                              CH.sub.3                                                                            CH.sub.3                                                                            3-CF.sub.3                                                                           186    --                                Comp'd 96                                                                              H      CH.sub.3                                                                              CH.sub.3                                                                            CH.sub.3                                                                            3,4-Cl.sub.2                                                                         186    --                                Comp'd 44                                                                              H      CH.sub.3                                                                              CH.sub.3                                                                            CH.sub.3                                                                            4-Cl  --     149                               Comp'd 49                                                                              CH.sub.3                                                                              CH.sub.3                                                                              H    H    3,4-Cl.sub.2                                                                         193    --                                Comp'd 85                                                                              CH.sub.3                                                                              CH.sub.3                                                                              H    H    3-CF.sub.3                                                                           --     193                               Comp'd 87                                                                              CH.sub.3                                                                              CH.sub.3                                                                              H    CH.sub.3                                                                            3-Cl  179    --                                ______________________________________                                          Note: "--" means that no measurement was conducted. ("--" will have the        same meaning in the subsequent Tables.)                                  

                  TABLE 1-C                                                        ______________________________________                                          ##STR26##                    (Ic)                                                                   Immune response                                                                potentiation activities                                  Sample                (Control = 100%)                                         compound                                                                               R.sub.1 R.sub.4 X.sub.n 0.2 μg/ml                                                                           1 μg/ml                             ______________________________________                                         Comp'd 141                                                                             H       H       3-Cl    750     842                                    Comp'd 137                                                                             H       H       3,4-I.sub.2                                                                            316     561                                    Comp'd 142                                                                             H       H       4-Cl    --      471                                    Comp'd 140                                                                             H       H       2-Cl    --      198                                    Comp'd 144                                                                             H       H       3,4-Cl.sub.2                                                                           405     663                                    Comp'd 145                                                                             H       H       3,5-Cl.sub.2                                                                           318     382                                    Comp'd 155                                                                             H       H       2-Cl, 4-CF.sub.3                                                                       208     439                                    Comp'd 160                                                                             H       CH.sub.3                                                                               3,4-Cl.sub.2                                                                           --      896                                    Comp'd 135                                                                             H       CH.sub.3                                                                               4-Cl    --      230                                    Comp'd 134                                                                             H       CH.sub.3                                                                               3-Cl    520     --                                     Comp'd 166                                                                             H       CH.sub.3                                                                               3,5-(CF.sub.3).sub.2                                                                   339     420                                    Comp'd 136                                                                             H       CH.sub.3                                                                               3-Cl, 4-CF.sub.3                                                                       527     --                                     Comp'd 167                                                                             H       CH.sub.3                                                                               H       --      267                                    Comp'd 138                                                                             CH.sub.3                                                                               H       3,4-Cl.sub.2                                                                           261     839                                    Comp'd 157                                                                             CH.sub.3                                                                               H       3,4-I.sub.2                                                                            239     266                                    ______________________________________                                    

For the sake of comparison, effects on in-vitro plaque forming cell response were also measured in the same manner with respect to the following compounds which are described in Japanese Patent Laid-Open No. 106893/1977 and J. Med. Chem., 24, 604-609 (1981). Results are shown in Table 1-D.

                  TABLE 1-D                                                        ______________________________________                                          ##STR27##                   (VII)                                                                   Immune response                                                                potentiation                                                                   activities (Con-                                                               trol = 100%)                                             Sample                  0.2      1                                             compound R.sub.1                                                                              R.sub.3                                                                               R.sub.4                                                                             X.sub.n  μg/ml                                                                              μg/ml                            ______________________________________                                         Comparative                                                                             H     H      H    2-F       78    --                                  Compound 1                                                                     Comparative                                                                             H     H      H    2,6-Cl.sub.2                                                                             82    126                                 Compound 2                                                                     Comparative                                                                             H     H      H    2,4,6-(CH.sub.3).sub.3                                                                  --     127                                 Compound 3                                                                     Comparative                                                                             H     CH.sub.3                                                                              CH.sub.3                                                                            2,4,6-(CH.sub.3).sub.3                                                                  121    132                                 Compound 4                                                                     Comparative                                                                             H     CH.sub.3                                                                              H    2,4,6-(CH.sub.3).sub.3                                                                  100    119                                 Compound 5                                                                     ______________________________________                                    

As apparent from Table 1-A-Table 1-D, the compounds of this invention showed activities higher than levamisole at a low concentration of 0.2 or 1 μg/ml in the above test in which levamisole required a concentration as high as about 20 μg/ml to exhibit potentiation activities. On the other hand, the comparative compounds exhibited substantially no activities.

Test 2

Effect on lymphocyte blstoenic response in vitro:

In an RPMI-1640 culture medium (0.2 ml) containing 5% of fetal calf serum (FCS) BALB/C mo spleen cells (1×10⁵) or thymus cells (2×10⁵) were cultured together with mitogen (Con A: 2.5 μg/ml; or LPS: 10 μg/ml) and a sample compound(1 μg/ml) for 48 hours in a CO₂ incubator (37° C.). Then, 0.5 μCi of ³ H-thymidine was added, followed by further cultivation for 18 hours. The radioactivity of ³ H-thymidine taken in the cells was thereafter measured Results are summarized in Table 2.

                  TABLE 2                                                          ______________________________________                                                   Incorporation ratio of .sup.3 H-thymidine                                     (Control = 100%)                                                               Spleen cells    Thymus cells                                          Sample compound                                                                           Con A      LPS        Con A                                         (1 μg/ml)                                                                              stimulation                                                                               stimulation                                                                               stimulation                                   ______________________________________                                         Compound 141                                                                              131        169        --                                            Compound 142                                                                              166        234        215                                           Compound 144                                                                              148        197        157                                           Compound 135                                                                              182        263        --                                            Compound 145                                                                              133        174        --                                            Compound 134                                                                              136        233        164                                           Compound 48                                                                               136        --         148                                           Compound 91                                                                               151        --         --                                            Compound 163                                                                              140        174        122                                           ______________________________________                                    

The compounds of this invention apparently stimulated the incorporation of ³ H-thymidine.

Test 3

Effect on lymphocyte blastogenic response in vivo:

A group of six BALB/C mice were used. A sample compound was orally administered at a daily dose of 0.25 mg/Kg, once a day, for 5 days. On the sixth day spleens were taken out. Spleen cells (2×10⁵) were cultured together with mitogen (Con A: 2.5 μg/ml; or LPS 10 μg/ml) to investigate the lymphocyte blastogenic response. Culturing conditions were the same as those employed in Test 2 and the measurement of the lymphocyte blastogenic response was effected in accordance with the method used in Test 2. Although levamisole required its administration at a dose of 2.5 mg/Kg/day to show its effects in the present test, the compounds of this invention showed promoting activities equal to or higher than levamisole at a dose one tenth of levamisole, i.e., at a dose of 0.25 mg/Kg/day (Table 3).

                  TABLE 3                                                          ______________________________________                                                     Incorporation ratio of .sup.3 H-thymidine                                      (Control: 100%)                                                    Sample compound                                                                              Con A stimulation                                                                           LPS stimulation                                     ______________________________________                                         Compound 136  240 ± 18  210 ± 9                                          Compound 167  155 ± 10  111 ± 9                                          Compound 134  310 ± 22  125 ± 9                                          Compound 51   142 ± 26   118 ± 12                                        Compound 49   195 ± 8   156 ± 4                                          Compound 91   256 ± 17   176 ± 16                                        Compound 44   155 ± 19  115 ± 6                                          ______________________________________                                    

Test 4

Effect on delayed-type allergic response:

A group of eight ddY mice were sensitized by injecting 2×10⁸ sheep erythrocytes subcutaneously in the back of each of the mice. On the fourth day after their sensitization, 5×10⁷ sheep erythrocytes were injected under the heel skin of one of the hind legs of each of the mice whereas a physiological saline was injected in the heel skin of the other hind leg. 24 hours later, the thickness of each paw was measured by a micrometer to determine the degree of swelling. Each sample compound was orally administered for 5 days, once a day, after passage of 2 hours from the sensitization. Results are shown in Table 4-A and 4-B. The compounds of this invention inhibited the delayed-type allergic response significantly by its oral administration at a dose of 0.1 mg/Kg/day.

                  TABLE 4-A                                                        ______________________________________                                                                 Degree of swelling (%)                                 Sample     Dose         (average value ±                                    Compound   (mg/Kg/day,po)                                                                              standard deviation)                                    ______________________________________                                         Control    --           29.0 ± 9.0                                          Compound 134                                                                              0.1          15.6 ± 4.0*                                         Compound 134                                                                              0.2          14.7 ± 4.82*                                        ______________________________________                                          *Significant at a level of P <0.05 against Control.                      

                  TABLE 4-B                                                        ______________________________________                                                                 Degree of swelling (%)                                 Sample     Dose         (average value ±                                    Compound   (mg/Kg/day,po)                                                                              standard deviation)                                    ______________________________________                                         Control    --           24.2 ± 6.9                                          Compound 44                                                                               0.1          17.1 ± 4.6*                                         ______________________________________                                          *Significant at a level of P <0.05 against Control.                      

Test 5

Effect on adjuvant arthritis:

(1) A group of eight Lewis male rats were employed. A suspension of 0.6 mg/0.1 ml of dead cells of Micobacterium tuberculosis in liquid paraffin was injected as an adjuvant in the heel skin of one of the hind legs of each of the rats, thereby inducing adjuvant arthritis. Besides, each sample compound was orally administered once a day for 20 days. On the 21^(st) day, the paw volumes of both hind legs of each of the rats were measured to determine the degree of swelling. Results are shown in Table 5-A.

(2) A suspension of 0.6 mg/0.1 ml of dead cells of Micobacterium tuberculosis in liquid paraffin was injected as an adjuvant in the heel skin of one of the hind legs of each of eight Sprague-Dawley male rats in a group, thereby inducing adjuvant arthritis. From the 21^(st) day after the injection of the adjuvant, each sample compound of this invention was orally administered everyday once a day. The volume of the paw of each hind leg, which was not injected with the adjuvant, was measured on the 7^(th) and 10^(th) days so that the degrees of swelling were determined. Results are shown in Table 5-B.

The compounds of this invention inhibited the swelling of the adjuvant non-injected legs and adjuvant-injected legs significantly when administered at a dose of 1 or 5 mg/Kg/day.

                  TABLE 5-A                                                        ______________________________________                                                         Degree of swelling (%)                                                         (average value ±                                                            standard deviation)                                                                  Adjuvant    Adjuvant                                     Sample   Dose         non-injected                                                                               injected                                     compound (mg/Kg/day,po)                                                                              leg         leg                                          ______________________________________                                         Control  --           173.1 ± 25.5                                                                            309.9 ± 27.1                              Comp'd 44                                                                               1            142.6 ± 29.0*                                                                           285.9 ± 44.9                              Comp'd 44                                                                               5            135.1 ± 27.3*                                                                           274.1 ± 35.4*                             ______________________________________                                          *Significant at a level of P <0.05 against Control.                      

                  TABLE 5-B                                                        ______________________________________                                                               Degree of swelling (%)                                                         (average value ±                                      Sample   Dose         standard deviation)                                      compound (mg/Kg/day,po)                                                                              7.sup.th day                                                                               10.sup.th day                                ______________________________________                                         Control  --           100.5 ± 31.1                                                                            89.9 ± 28.5                               Comp'd 134                                                                              5             66.0 ± 32.8*                                                                           59.0 ± 27.1*                              ______________________________________                                          *Significant at a level of P <0.05 against Control.                      

Test 6:

Side effects and blood levels:

To each of four Wistar male rats in a group, each sample compound was orally administered at a dose of 300 mg/Kg, once a day, for 4 days to observe changes in general behaviors and at the same time, to investigate influence on body weight, liver weight and serum cholesterol level. The serum cholesterol level was measured by a Centriphichem Autoanalyzer, using a cholesterol measurement kit marketed by Baker, Inc. Compound 44 and 134 and for certain tests, Compound 2, 3, 30, 31 and 32, were all employed as compounds of this invention, while a compound represented by the general formula (X), in which R₁ =R₃ =R₄ =H and (X)_(n) =3,4--Cl₂ (Comparative Compound 6), and a compound represented also by the general formula (X), in which R₁ =R₃ =R₄ =H and (X)_(n) =3,4-CF₃ (Comparative Compound 7), were both used as comparative compounds. In certain tests, levamisole was also used as a comparative compound. The blood levels of the individual sample compounds were also compared after their single administration and after their administration for four days. Their blood levels were measured by means of a high-performance liquid chromatography.

(1) Effect on the general behaviors:

Although no changes were observed on the general behaviors in the groups administered respectively with the compounds of this invention and Comparative Compound 6, dacryorrhea, dacryohemorrhea, sedation, ataxia and tremor were observed in the group administered with Comparative Compound 7. In the group administered with levamisole, one half of the animals resulted in death.

(2) Effect on the body weight:

Body weights both before administration of the sample compounds and after their continuous administration for 4 days are shown in Table 6-A-Table 6-C.

                  TABLE 6-A                                                        ______________________________________                                                         Body weight, (g)                                                               (average value ±                                                            standard deviation)                                                                  Before     After                                         Sample  Dose          administ-  administration                                compound                                                                               (mg/Kg/day,po)                                                                               ration     for 4 days                                    ______________________________________                                         Control --            79.0 ± 3.5                                                                              93.0 ± 3.4                                Comp'd 30                                                                              300           79.0 ± 2.0                                                                              91.0 ± 0.8                                Control --            91.3 ± 1.5                                                                             104.0 ± 3.7                                Comp'd 31                                                                              300           91.3 ± 5.5                                                                             102.8 ± 7.8                                Control --            113.3 ± 1.5                                                                            128.5 ± 3.0                                Comp'd 32                                                                              300           113.8 ± 1.3                                                                            122.0 ± 6.5                                Comp'd 3                                                                               300           114.0 ± 5.7                                                                            126.0 ± 8.8                                Control --            87.0 ± 5.1                                                                             102.8 ± 5.9                                Comp'd 2                                                                               300           87.3 ± 2.8                                                                             102.0 ± 1.6                                Comp.                                                                          Comp'd 6                                                                               300           87.3 ± 2.5                                                                              89.5 ± 3.0*                               Control --            93.3 ± 5.7                                                                             108.3 ± 4.9                                Levamisole                                                                             100           93.5 ± 4.7                                                                              99.5 ± 2.5*                               Control --            111.0 ± 5.3                                                                            128.5 ± 7.0                                Comp.                                                                          Comp'd 7                                                                               300           110.0 ± 2.3                                                                            115.3 ± 8.2*                               ______________________________________                                          *Significant at a level of P < 0.05 against Control.                     

                                      TABLE 6-B                                    __________________________________________________________________________                    Test 1        Test 2                                            Sample                                                                               Dose     Before After  Before After                                      compound                                                                             (mg/Kg/day,po)                                                                          administration                                                                        administration                                                                        administration                                                                        administration                             __________________________________________________________________________     Control                                                                              --       84.5 ± 3.1                                                                         100.5 ± 2.5                                                                        87.0 ± 5.1                                                                         102.8 ± 5.9                             Comp'd 44                                                                            300      84.0 ± 1.4                                                                         100.0 ± 2.9                                                                        87.0 ± 2.2                                                                         102.5 ± 3.4                             Comp. 300      84.3 ± 6.1                                                                         88.8 ± 6.4*                                                                        87.3 ± 2.5                                                                         89.5 ± 3.0*                             Comp'd 6                                                                       __________________________________________________________________________      Each value indicates the average body weight (g) of 4 rats in the same         group ± standard deviation.                                                 *Significant at a level of P <0.05 against Control.                      

                                      TABLE 6-C                                    __________________________________________________________________________                    Test 1        Test 2                                            Sample                                                                               Dose     Before After  Before After                                      compound                                                                             (mg/Kg/day,po)                                                                          administration                                                                        administration                                                                        administration                                                                        administration                             __________________________________________________________________________     Control                                                                              --       79.3 ± 1.0                                                                         97.0 ± 3.5                                                                         81.8 ± 2.6                                                                         96.0 ± 2.8                              Comp'd 134                                                                           300      79.5 ± 1.0                                                                         95.8 ± 4.2                                                                         82.0 ± 5.9                                                                         92.0 ± 5.9                              Comp. 300      79.3 ± 1.5                                                                         89.5 ± 3.0*                                                                        --     --                                         Comp'd 6                                                                       __________________________________________________________________________      Each value indicates the average body weight (g) of 4 rats in the same         group ± standard deviation.                                                 *Significant at a level of P <0.05 against Control.                      

Although neither Compound 44 nor Compound 134 gave any effects to the body weight, Comparative Compound 6 decreased the body weight significantly against Control. Levamisole decreased the body weight significantly against Control even when administered at 100 mg/Kg/day.

(3) Effect on the liver weight

Results are shown in Table 7-A and Table 7-B. Although Compound 1 did not give any significant effect on the liver weight compared with Control, Comparative Compound 6 increased the liver weight significantly against Control.

                                      TABLE 7-A                                    __________________________________________________________________________                    Test 1        Test 2                                            Sample                                                                               Dose     Liver weight                                                                            Increase                                                                            Liver weight                                                                           Increase                                  compound                                                                             (mg/Kg/day,po)                                                                          (g/100 g B.W.**)                                                                        (%)  (g/100 g B.W.)                                                                         (%)                                       __________________________________________________________________________     Control                                                                              --       4.22 ± 0.03                                                                          --   4.13 ± 0.20                                                                         --                                        Comp'd 44                                                                            300      4.33 ± 0.07                                                                          2.6  4.74 ± 0.65                                                                         14.8                                      Comp. 300      5.35 ± 0.43*                                                                         26.8 5.71 ± 0.27*                                                                        38.3                                      Comp'd 6                                                                       __________________________________________________________________________      Each liver weight indicates the average value of 4 rats in the same group      ± standard deviation.                                                       *Significant at a level of P <0.05 against Control.                            **B.W. stands for "body weight".                                         

                                      TABLE 7-B                                    __________________________________________________________________________                    Test 1        Test 2                                            Sample                                                                               Dose     Liver weight                                                                            Increase                                                                            Liver weight                                                                           Increase                                  compound                                                                             (mg/Kg/day,po)                                                                          (g/100 g B.W.**)                                                                        (%)  (g/100 g B.W.)                                                                         (%)                                       __________________________________________________________________________     Control                                                                              --       4.30 ± 0.06                                                                          --   4.10 ± 0.22                                                                         --                                        Comp'd 134                                                                           300      4.43 ± 0.21                                                                          3.0  4.13 ± 0.14                                                                         0.7                                       Comp. 300      5.62 ± 0.17*                                                                         30.7 5.50 ± 0.44*                                                                        34.1                                      Comp'd 6                                                                       __________________________________________________________________________      Each liver weight indicates the average value of 4 rats in the same group      ± standard deviation.                                                       *Significant at a level of P <0.05 against Control.                            **B.W. stands for "body weight".                                         

(4) Effect on the serum cholesterol level:

Test results are shown in Table 8-A and Table 8-B. Neither Compound 44 nor Compound 134 gave any significant effects to the serum cholesterol level compared with Control, Comparative Compound 6 and 7 and Levamisole increased the cholesterol level significantly against Control.

                                      TABLE 8-A                                    __________________________________________________________________________                    Test 1      Test 2                                              Sample                                                                               Dose     Cholesterol                                                                           Increase                                                                            Cholesterol                                                                           Increase                                     compound                                                                             (mg/Kg/day,po)                                                                          (mg/dl)                                                                               (%)  (mg/dl)                                                                               (%)                                          __________________________________________________________________________     Control                                                                              --       83.4 ± 7.8                                                                         --   75.2 ± 6.7                                                                         --                                           Comp'd 44                                                                            300      81.3 ± 8.4                                                                         -2.5 82.6 ± 7.1                                                                         9.8                                          Comp. 300      168.3 ± 16.1*                                                                      101.8                                                                               157.1 ± 21.0*                                                                      108.9                                        Comp'd 6                                                                       Control                                                                              --       63.0 ± 6.6                                                                         --   63.0 ± 3.5                                                                         --                                           Comp. 300      83.2 ± 6.2*                                                                        32.1 83.9 ± 5.3*                                                                        33.2                                         Comp'd 7                                                                       Control                                                                              --       73.4 ± 7.5                                                                         --                                                       Levamisole                                                                           100      89.0 ± 4.9*                                                                        21.3                                                     __________________________________________________________________________      Each liver weight indicates the average value of 4 rats in the same group      ± standard deviation.                                                       *Significant at a level of P <0.05 against Control.                      

                                      TABLE 8-B                                    __________________________________________________________________________                    Test 1      Test 2                                              Sample                                                                               Dose     Cholesterol                                                                           Increase                                                                            Cholesterol                                                                           Increase                                     compound                                                                             (mg/Kg/day,po)                                                                          (mg/dl)                                                                               (%)  (mg/dl)                                                                               (%)                                          __________________________________________________________________________     Control                                                                              --       70.6 ± 7.1                                                                         --   66.2 ± 2.9                                                                         --                                           Comp'd 134                                                                           300      78.5 ± 5.8                                                                         11.2 72.9 ± 6.9                                                                         10.1                                         Comp. 300      134.5 ± 8.3*                                                                       90.5 138.2 ± 17.0*                                                                      108.8                                        Comp'd 6                                                                       __________________________________________________________________________      Each cholesterol level indicates the average value of 4 rats in the same       group ± standard deviation.                                                 *Significant at a level of P <0.05 against Control.                      

(5) Change in blood level by repeated administration:

Table 9 shows blood levels on the 1^(st) and 2^(nd) hours after each of a single administration and an administration for 4 days, once a day. Although the blood levels of Compounds 44 and 129 were found to be close to their blood levels after their single administration even after the administration for 4 days, the blood levels of Comparative Compounds 6 and 7 dropped remarkably by their repeated administration.

                                      TABLE 9                                      __________________________________________________________________________                    Blood level (μg/ml)                                          Sample                                                                               Dose     Single administration                                                                       Administration for 4 days                          compound                                                                             (mg/Kg/day,po)                                                                          1 hour later                                                                         2 hours later                                                                         1 hour later                                                                         2 hours later                                __________________________________________________________________________     Comp'd 44                                                                            300      --    12.98 ± 3.81                                                                       --    10.48 ± 1.34                              Comp'd 134                                                                           300      4.48 ± 2.32                                                                       12.15 ± 2.18                                                                       9.75 ± 4.86                                                                       7.70 ± 0.79                               Comp. 300      8.27 ± 2.40                                                                       4.61 ± 0.74                                                                        0.38 ± 0.33                                                                       0.16 ± 0.24                               Comp'd 6                                                                       Comp. 300      8.48 ± 1.91                                                                       10.80 ± 3.53                                                                       3.03 ± 2.08                                                                       2.73 ± 1.14                               Comp'd 7                                                                       __________________________________________________________________________      Each blood level indicates the average value of 4 rats in the same group       ± standard deviation.                                                 

The compounds of this invention may be administered, as they are or in various dosage forms, orally or parenterally (for example, by their intramuscular, subcutaneous, intravenous, rectal or cutaneous administration). As their dosable preparation forms, they may be formed into solid preparations such as tablets, sugar-coated tablets, film-coated tablets, hard and soft capsules, troches, pills, granules and powders; semi-solid preparations such as suppositories, plasters and ointments; and liquid preparations such as injectable solutions, syrups, inhalants, emulsions and suspensions. Although the compounds of this invention may be formed into the above-described preparations without any additional pharmaceutically-effective ingredients, one or more other pharmaceutically-effective ingredients such as nonsteroid analgesic and artiphlogistic agents may also be incorporated in combination.

[EXAMPLES]

The present invention will hereinafter be described further by the following Referential Examples and Examples.

Referential Example 1:

Dissolved in toluene were 3.5 g (0.02 mole) of 3,4-dichloro-N-methylaniline and a catalytic amount of pyridine, followed by a dropwise addition of 1.9 g (0.022 mole) of diketene at 50° C. After completion of the the dropwise addition, the resultant mixture was heated under reflux for 3 hours. The reaction mixture was cooled, and its organic layer was then washed with water, water, a 10% aqueous solution of hydrochloric acid and a 5% aqueous solution of sodium hydrogencarbonate in order. The thus-washed organic solution was dried nd concentrated to obtain 3',4'-dichloro-N-methylacetoacetoanilide.

Example 1: ##STR28##

(i) Suspended in carbon tetrachloride were 2.6 g (0.01 mole) of the 3',4'-dichloro-N-methylacetoacetoanilide obtained in Referential Example 1 and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant mixture was heated under reflux for 1 hour. The reaction mixture was then washed with water, dried and concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.0 g (0.01 mole) of imidazolidine-2-thione. The mixture was then heated under reflux for 3 hours. Precipitated crystals were collected by filtration, recrystallized from ethanol and then dried under reduced pressure, thereby obtaining 3.4 g of 3',4'-dichloro-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 1) [yield: 89.5%]. Melting point: 275°-276° C.

(ii) Dissolved in water was 1.9 g (0.005 mole) of the thus-obtained hydrochloride, followed by a dropwise addition with stirring of a 10% aqueous solution of caustic soda at room temperature. Resultant crystals were collected by filtration and washed with a great deal of water to purify same. The thus-washed crystals were dried under reduced pressure to obtain 1.4 g of 3',4'-dichloro-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]-thiazole-2-carboxyanilide (yield: 82.4%). Melting point: 118°-122° C.

Example 2: ##STR29##

(i) Suspended in carbon tetrachloride were 1.4 g (0.01 mole) of 3',5'-dichloro-N-methylacetoacetoanilide, obtained in the same manner as in Referential Example 1, and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant mixture was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione. The resultant mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, recrystallized from isopropanol and then dried under reduced pressure, thereby obtaining 3.0 g of 3',5'-dichloro-N,3,6,6-tetramethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 2) [yield: 75.0%]. Melting point: 222°-230° C.

(ii) Dissolved in water was 2.0 g (0.005 mole) of the above-obtained hydrochloride, followed by a dropwise addition with stirring of a 20% aqueous solution of potassium carbonate at room temperature. Resultant crystals were collected by filtration and then washed with a great deal of water for its purification. The thus-purified crystals were dried under reduced pressure to obtain 1.5 g of 3',5'-dichloro-N,3,6,6-tramethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide (yield: 78.9%).

Melting point: 169° C.

Example 3: ##STR30##

Dissolved in diethyl ether was 2.6 g (0.01 mole) of N-methyl-4'-trifluoromethylacetoacetoanilide obtained in the same manner as in Referential Example 1, followed by a dropwise addition of 1.5 g (0.011 mole) of sulfuryl chloride at -5° C. The resultant mixture was stirred at -10°--5° C. for 30 minutes. The reaction mixture was then poured into ice water, neutralized with sodium hydrogencarbonate and extracted with toluene. The organic layer was dried an concentrated. The residue was dissolved in methyl ethyl ketone, to which 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione was added. The mixture was heated under reflux for 3 hours. Precipitate crystals were collected by filtration, washed with acetone and then dried under reduced pressure, thereby obtaining 3.7 g of N,3,6,6-tetramethyl-4'-trifluoromethyl-5,6-dihydroimidazo- [2,1-b]-thiazole-2-carboxyanilide hydrochloride (Compound 3) [yield: 92.5%]

Melting point: 195°-198° C.

Example 4: ##STR31##

Suspended in carbon tetrachloride were 2.7 g (0.01 mole) of 3',4'-dichloro-N-ethylacetoacetoanilide, obtained in the same manner as in Referential Example 1, and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant mixture was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole of 4,4-dimethylimidazolidine-2-thione. The resultant mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, washed with acetone and then dried under reduced pressure, thereby obtaining 3.3 g of 3',4'-dichloro-N-ethyl-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 4) [yield: 78.6%].

Melting point: 210°-214° C.

Example 5: ##STR32##

Following the procedure of Example 2, 2.6 g (0.01 mole) of 3',4'-dichloro-N-methylacetoacetanilide obtained in Referential Example 1 was chlorinated. The resultant oily substance was dissolved in methyl ethyl ketone, followed by an addition of 1.2 g (0.01 mole) of 4-methylimidazolidine-2-thione. The resulting mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, followed by its washing with acetone to obtain 3.6 g of 3',4'-dichloro-N,3,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 5) [yield: 92.3%].

Melting point: 230°-231° C.

Example 6: ##STR33##

Suspended in carbon tetrachloride were 3.2 g (0.01 mole) of N-methyl-3',5'-bis(trifluoromethyl)acetoacetoanilide, obtained in the same manner as in Referential Example 1, and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant mixture was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione. The resultant mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, washed with acetone and then dried under reduced pressure, thereby obtaining 3.5 g of N,3,5,6-tetramethyl-3',5'-bis(trifluoromethyl)-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 6) [yield: 74.5%].

Melting point: 214°-218° C.

Examples 7-43:

The following compounds were prepared in the same manner as in Referential Example 1 and Examples 1 -6.

    __________________________________________________________________________                                              Melting point                         No.                                                                               R.sub.1                                                                           R.sub.2                                                                          R.sub.3                                                                           R.sub.4                                                                           R.sub.5                                                                            X.sub.n  Appearance    (°C.)                          __________________________________________________________________________     7  H  H H  H  CH.sub.3                                                                           3,4-(OCH.sub.3).sub.2                                                                   Light brownish crystals                                                                      249-253                               8  H  H H  H  CH.sub.3                                                                           4-OC.sub.2 H.sub.5                                                                      White powder  205-209                               9  H  H H  H  CH.sub.3                                                                           3,5-(OCH.sub.3).sub.2                                                                   Light Brownish powder                                                                        222-224                               10 H  H H  H  CH.sub.3                                                                           H        Light brownish crystals                                                                      240-242                               11 H  H H  H  CH.sub.3                                                                           4-Cl     Slightly yellowish                                                                           257-260                                                          platy crystals                                      12 H  H H  H  CH.sub.3                                                                           3-OC.sub.3 H.sub.7 -i                                                                   White powder  209-210                               13 H  H H  H  CH.sub.3                                                                           3-CF.sub.3                                                                              White powder  228-235                               14 H  H H  H  CH.sub.3                                                                           2-CH.sub.3, 4-Cl                                                                        Yellowish granular crystals                                                                  267-270                               15 H  H H  H  CH.sub.3                                                                           2-Cl, 4-CF.sub.3                                                                        Brown powder  184-192                               16 H  H H  H  CH.sub.3                                                                           3-Cl     Light yellow powder                                                                          210-215                               17 H  H H  H  CH.sub.3                                                                           3,5-(CF.sub.3).sub.2                                                                    Light yellow powder                                                                          274-276                               18 H  H H  H  CH.sub.3                                                                           4-CF.sub.3                                                                              Yellow powder 235-239                               19 H  H H  H  C.sub.2 H.sub.5                                                                    3,4-Cl.sub.2                                                                            Light brownish crystals                                                                      255-258                               20 H  H H  H  C.sub.2 H.sub.5                                                                    3-CF.sub.3                                                                              Light brownish crystals                                                                      232-234                               21 H  H H  H  C.sub.2 H.sub.5                                                                    2-Cl, 4-CF.sub.3                                                                        Brown crystals                                                                               220-229                               22 H  H H  H  C.sub.3 H.sub.7                                                                    3,4-Cl.sub.2                                                                            Milky white crystals                                                                         250-254                               23 H  H H  H  C.sub.3 H.sub.7 -i                                                                 3-OC.sub.3 H.sub.7 -i                                                                   White powder  187-189                               24 H  H H  H  C.sub.3 H.sub.7 -i                                                                 3,4-Cl.sub.2                                                                            Milky white crystals                                                                         250-254                               25 H  H H  H  C.sub.3 H.sub.7 -i                                                                 4-Cl     White crystals                                                                               228-231                               26 H  H H  H  C.sub.3 H.sub.7 -i                                                                 3-CF.sub.3                                                                              Light brownish crystals                                                                      197-198                               27 H  H H  H  C.sub.3 H.sub.7 -i                                                                 3,5-Cl.sub.2                                                                            White powder  250-254                               28 CH.sub.3                                                                          H CH.sub.3                                                                          H  CH.sub.3                                                                           4-F      Milky white powder                                                                           195-198                               29 H  H CH.sub.3                                                                          H  CH.sub.3                                                                           3-Cl     Dark yellow powder                                                                           unmeasurable                          30 H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                           3-CF.sub.3                                                                              Milky white powder                                                                           202-210                               31 H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                           3,4-Cl.sub.2                                                                            Light brownish crystals                                                                      202-206                               32 H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                           3,5-(CF.sub.3).sub.2                                                                    Yellowish brown powder                                                                       168-170                               33 H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                           2-Cl, 4-CF.sub.3                                                                        Light brownish crystals                                                                      222-224                               34 H  H CH.sub.3                                                                          CH.sub.3                                                                          C.sub.2 H.sub.5                                                                    2-Cl, 4-CF.sub.3                                                                        Light brownish platy crystals                                                                230-235                               35 H  H CH.sub.3                                                                          CH.sub.3                                                                          C.sub.2 H.sub.5                                                                    3-CF.sub.3                                                                              Yellow crystals                                                                              51-52                                 36 H  H CH.sub.3                                                                          CH.sub.3                                                                          C.sub.3 H.sub.7                                                                    3,4-Cl.sub.2                                                                            White crystals                                                                               214-218                               37 H  H CH.sub.3                                                                          CH.sub.3                                                                          C.sub.3 H.sub.7 -i                                                                 3,4-Cl.sub.2                                                                            Milky white crystals                                                                         220-225                               38 H  H CH.sub.3                                                                          CH.sub.3                                                                          C.sub.3 H.sub.7 -i                                                                 4-Cl     White crystals                                                                               245-250                               39 H  H CH.sub.3                                                                          CH.sub.3                                                                          C.sub.3 H.sub.7 -i                                                                 3-CF.sub.3                                                                              Light yellowish crystals                                                                     unmeasurable                          40 H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                           4-NO.sub.2                                                                              Light yellowish crystals                                                                     177-182                               41 H  H CH.sub. 3                                                                         CH.sub.3                                                                          CH.sub.3                                                                           4-F      Milky white powder                                                                           184-186                               42 H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                           3,5-Cl.sub.2,4-C.sub.5 H.sub.11 O                                                       Brown powder  209-212                               43 H  H CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                           2,3,4,5,6-F.sub.5                                                                       Light yellowish powder                                                                       216-222                               __________________________________________________________________________

Referential Example 2:

Dissolved in toluene was 3.1 g (0.02 mole) of 4-chloro-N-methyl-benzylamine, followed by an addition of a catalytic amount of pyridine and a further dropwise addition of 1.8 g (0.022 mole) of diketene at room temperature. After stirring the reaction mixture at room temperature for 3 hours, it was poured in water and then extracted with toluene. Subsequent to purification, N-methyl-N-(4-chlorobenzyl)acetamide was obtained in an oily form.

Example 44: ##STR34##

(i) Suspended in carbon tetrachloride were 4.0 g (0.017 mole) of N-methyl-N-(4-chlorobenzyl)acetoacetamide obtained in Referential Example 2, 2.3 g (0.017 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and then extracted with carbon tetrachloride. The carbon tetrachloride solution was purified, dried and concentrated, thereby obtaining an oily crude product The crude product was purified on a silica gel column (c-300, n-hexane-ethyl acetate) to obtain 3.5 g of oily N-methyl-N-(4-chlorobenzyl)-2-chloroacetamide (n_(D) ²⁰ : 1.5336). The reaction product was then dissolved together with 1.7 g (0.013 mole) of 4,4-dimethylimidazolidine-2-thione in methyl ethyl ketone. The resultant mixture was heated under reflux for 3 hours. After cooling, the resultant precipitate was collected by filtration, washed with acetone and then recrystallized from isopropanol/isopropyl ether, thereby obtaining 4.8 g of N-(4-chlorobenzyl)-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2carboxamide hydrochloride as (Compound 44)

[melting point: 187°-190° C.; white crystals].

(ii) Dissolved in water was 3.9 g (0.01 mole) of the above-obtained hydrochloride. While stirring the thus-prepared aqueous solution at room temperature, a 10% aqueous solution of caustic soda was added dropwise. Resulting crystals were collected by filtration and then washed with a great deal of water to purify same. The crystals were thereafter dried under reduced pressure to obtain 3.3 g of N-(4-chlorobenzyl)-N,3,6,6-tetramethyl-5,6-dihydroimidazo[2,1-b)-thiazole-2-carboxamide (melting point: 139° C.; light yellowish powdery crystals).

Example 45: ##STR35##

Suspended in carbon tetrachloride were 2.3 g (0.01 mole) of N-(4-chlorobenzyl)acetoacetamide obtained in the same manner as in Referential Example 2, 1.3 g (0.01 mole) of N-chlorosuccinimide an a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. The reaction mixture was then poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 1.0 g (0.01 mole) of imidazolidine-2-thione were suspended in methyl ethyl ketone and the resultant suspension was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration, washed with acetone and then recrystallized from isopropyl alcohol/isopropyl ether, thereby obtaining 2.8 g of N-(4-chlorobenzyl)-3-methyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 45).

Melting point: 241°-242° C. White crystals.

Example 46: ##STR36##

Suspended in carbon tetrachloride were 2.6 g (0.01 mole) of N-(3-trifluoromethylbenzyl)acetoacetamide obtained in the same manner as in Referential Example 2, 1.3 g (0.01 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 1.0 g (0.01 mole) of imidazolidine-2-thione were suspended in methyl ethyl ketone and the resultant suspension was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration, washed with acetone and then recrystallized from ethanol, thereby obtaining 2.5 g of 3-methyl-N-(3-trifluoromethylbenzyl)-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 46)

[melting point:210°-216° C.; colorless prism-like crystals].

Example 47: ##STR37##

Suspended in carbon tetrachloride were 2.5 g (0.01 mole) of N-ethyl-N-(4-chlorobenzyl)acetoacetamide obtained in the same manner as in Referential Example 2, 1.3 g (0.01 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione were dissolved in methyl ethyl ketone and the resultant solution was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration, washed with acetone and then recrystallized from isopropanol/isopropyl ether, thereby obtaining 2.7 g of N-(4-chlorobenzyl)-N-ethyl-3,6,6-trimethyl-5,6-dihydroimido[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 47)

[melting point: 178°-181° C.; white crystals].

Example 48: ##STR38##

Suspended in carbon tetrachloride were 2.6 g (0.01 mole) of N-methyl-N-(3,4-dichlorobenzyl)acetoacetamide obtained in the same manner as in Referential Example 2, 1.3 g (0.01 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 1.0 g (0.01 mole) of imidazolidine-2-thione were suspended in methyl ethyl ketone and the resultant suspension was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration, washed with acetone and then recrystallized from ethanol, thereby obtaining 3.1 g of N-(3,4-dichlorobenzyl)-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 48)

[melting point: 146°-148° C; light yellowish needle-like crystals].

Example 49: ##STR39##

Suspended in carbon tetrachloride were 5.2 g (0.02 mole) of N-(3,4-dichlorobenzyl)acetoacetamide obtained in the same manner as in Referential Example 2, 2.7 g (0.02 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 2.6 g (0.02 mole) of 4,5-dimethylimidazolidine-2-thione were dissolved in methyl ethyl ketone and the resultant solution was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration add then washed and purified with a great deal of acetone, thereby obtaining N-(3,4-dichlorobenzyl)-3,5,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 49) [melting point: 148°-152° C.; white crystals].

Example 50: ##STR40##

Suspended in carbon tetrachloride were 4.8 g (0.02 mole) of N-(3-chlorobenzyl)-N-methylacetamide obtained in the same manner as in Referential Example 2, 2.7 g (0.02 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. It was then poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 2.4 g (0.02 mole) of 4-methylimidazolidine-2-thione were dissolved in methyl ethyl ketone and the resultant solution was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration and then washed and purified with acetone and isopropyl ether, thereby obtaining N-(3-chlorobenzyl)-N,3,6-trimethyl-5,6-dihydroimidazo[2,1-b]-hiazole-2-carboxamide hydrochloride (Compound 50)

[melting point: 41°-47° C.; brownish glassy matter].

Example 51: ##STR41##

(i) Suspended in carbon tetrachloride were 5.2 g (0.02 mole) of N-(2,4-dichlorobenzyl)-N-methylacetamide obtained in the same manner as in Referential Example 2, 2.7 g (0.02 mole) of N-chlorosuccinimide and a small amount of benzoyl peroxide. The suspension was heated under reflux for 1 hour. After cooling the reaction mixture, it was poured into water and extracted with carbon tetrachloride. The carbon tetrachloride solution was washed with water, dried and then concentrated. The resultant oily substance was provided for the following reaction without purifying same beforehand. Namely, the thus-obtained compound and 1.0 g (0.01 mole) of imidazolidine-2-thione were suspended in methyl ethyl ketone and the resultant suspension was heated under reflux for 3 hours. After cooling the reaction mixture, the resultant precipitate was collected by filtration and then washed and purified with acetone, thereby obtaining 5.3 g of N-(2,4-dichlorobenzyl)-N,3-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide hydrochloride (Compound 51)

[melting point: 251°-255° C.; colorless powder].

(ii) Dissolved in water was 3.6 g (0.01 mole) of the thus-obtained 2-[N-methyl-N-(2,4-dichlorobenzyl)carbmoyl]-3-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride. While stirring the solution at room temperature, aqueous ammonia was added dropwise. The resultant precipitate was collected by filtration and then washed and purified with a great deal of water, thereby obtaining 3.0 g of N-(2,4-dichlorobenzyl)-N,3-dimethyl-5,6-dihydrommidazo[2,1-b]thiazole-2-carboxamide

(melting point: 55°-60° C.; light yellowish crystals).

Examples 52-133:

The following compounds were prepared in the same manner as in Referential Example 2 and Examples 44-51.

    __________________________________________________________________________      ##STR42##                                                                     Com-                                                                           pound                                                   Melting point          No. R.sub.1                                                                           R.sub.2                                                                          R.sub.3                                                                           R.sub.4                                                                              R.sub.6                                                                              A      X.sub.n                                                                               Appearance        (°C.)           __________________________________________________________________________     52  H  H H  H     H     CH.sub.2                                                                              H      White prism-like crystals                                                                        260-270                53  H  H H  H     H     CH.sub.2                                                                              2-Cl   Black prism-like crystals                                                                        242-250                54  H  H H  H     H     CH.sub.2                                                                              3-Cl   White powder      233-235                55  H  H H  H     H     CH.sub.2                                                                              2,4-Cl.sub.2                                                                          Colorless crystals                                                                               275                    56  H  H H  H     H     CH.sub.2                                                                              3,4-Cl.sub.2                                                                          Colorless fine needle-like                                                                       273stals               57  H  H H  H     H     CH.sub.2                                                                              4-CH.sub.3                                                                            White powder      233-235                58  H  H H  H     H     CH.sub.2                                                                              4-OCH.sub.3                                                                           Light yellowish crystals                                                                         192-194                59  H  H H  H     H     CH.sub.2                                                                              4-NO.sub.2                                                                            White powder      243-248                60  H  H H  H     H     CH.sub.2                                                                              3,5-Cl.sub.2                                                                          Milky white crystals                                                                             250-253                61  H  H H  H     CH.sub.3                                                                             CH.sub.2                                                                              H      White prism-like crystals                                                                        187-189                62  H  H H  H     CH.sub.3                                                                             CH.sub.2                                                                              2-Cl   Light yellowish powder                                                                           189-192                63  H  H H  H     CH.sub.3                                                                             CH.sub.2                                                                              4-Cl   Light yellowish prism-like                                                                       126-130s               64  H  H H  H     CH.sub.3                                                                             CH.sub.2                                                                              4-CH.sub.3                                                                            Light brownish crystals                                                                          195-197                65  H  H H  H     CH.sub.3                                                                             CH.sub.2                                                                              4-OCH.sub.3                                                                           White crystals    118-119                66  H  H H  H     CH.sub.3                                                                             CH.sub.2                                                                              3-Cl   Yellowish brown glassy                                                                           52-58r                 67  H  H H  H     CH.sub.3                                                                             CH.sub.2                                                                              3-CF.sub.3                                                                            Yellowish brown crystals                                                                         31-34                  68  H  H H  H     CH.sub.3                                                                             CH.sub.2                                                                              3,5-Cl.sub.2                                                                          Milky white crystals                                                                             194-195                69  H  H H  H     CH.sub.3                                                                             CH.sub.2                                                                              4-F    Light brownish powder                                                                            173-175                70  H  H H  H     CH.sub.3                                                                             CH.sub.2                                                                              4-CF.sub.3                                                                            Milky white powder                                                                               212-215                71  H  H H  H     CH.sub.3                                                                             CH.sub.2                                                                              4-OC.sub.2 H.sub.5                                                                    Milky white powder                                                                               179-180                72  H  H H  H     CH.sub.3                                                                             CH.sub.2                                                                              4-C.sub.2 H.sub.5                                                                     Light brownish crystals                                                                          195-200                73  H  H H  H     CH.sub.3                                                                             CH.sub.2                                                                              4-NO.sub.2                                                                            Pinkish powder    236-238                74  H  H H  H     C.sub.2 H.sub.5                                                                      CH.sub.2                                                                              4-Cl   White crystals    202-205                75  H  H H  H     C.sub.2 H.sub.5                                                                      CH.sub.2                                                                              3,4-Cl.sub.2                                                                          Milky white crystals                                                                             247-250                76  H  H H  H     C.sub.2 H.sub.5                                                                      CH.sub.2                                                                              3-CF.sub.3                                                                            Light brownish crystals                                                                          170-175                77  H  H H  H     n-C.sub.3 H.sub.7                                                                    CH.sub.2                                                                              3,4-Cl.sub.2                                                                          Milky white crystals                                                                             233-237                78  H  H H  H     i-C.sub.3 H.sub.7                                                                    CH.sub.2                                                                              4-Cl   White crystals    225-230                79  H  H H  H     i-C.sub.3 H.sub.7                                                                    CH.sub.2                                                                              3-Cl   Light brownish crystals                                                                          202-205                80  H  H H  H     i-C.sub.3 H.sub.7                                                                    CH.sub.2                                                                              3-CF.sub.3                                                                            Yellowish crystals                                                                               233-236                81  H  H H  H     i-C.sub.4 H.sub.9                                                                    CH.sub.2                                                                              4-Cl   White crystals    237-238                82  H  H CH.sub.3                                                                          H     H     CH.sub.2                                                                              3-Cl   Milky white powder                                                                               148-150                83  CH.sub.3                                                                          H CH.sub.3                                                                          H     H     CH.sub.2                                                                              2,4-Cl.sub.2                                                                          White powder      170-172                84  CH.sub.3                                                                          H CH.sub.3                                                                          H     H     CH.sub.2                                                                              4-Cl   White powder      166-167                85  CH.sub.3                                                                          H CH.sub.3                                                                          H     H     CH.sub.2                                                                              3-CF.sub.3                                                                            Light brownish glassy                                                                            unmeasurable           86  CH.sub.3                                                                          H CH.sub.3                                                                          H     H     CH.sub.2                                                                              3-Cl   White crystals    171-173                87  CH.sub.3                                                                          H CH.sub.3                                                                          H     CH.sub.3                                                                             CH.sub.2                                                                              3-Cl   Brownish glassy matter                                                                           unmeasurable           88  H  H CH.sub.3                                                                          CH.sub.3                                                                             H     CH.sub.2                                                                              3-Cl   Yellowish brown powder                                                                           80-93                  89  H  H CH.sub.3                                                                          CH.sub.3                                                                             H     CH.sub.2                                                                              4-Cl   Slightly brownish                                                                                70-79als               90  H  H CH.sub.3                                                                          CH.sub.3                                                                             H     CH.sub.2                                                                              2,4-Cl.sub.2                                                                          White crystals    219-222                91  H  H CH.sub.3                                                                          CH.sub.3                                                                             H     CH.sub.2                                                                              3,4-Cl.sub.2                                                                          Light yellowish crystals                                                                         107-115                92  H  H CH.sub.3                                                                          CH.sub.3                                                                             H     CH.sub.2                                                                              3-CF.sub.3                                                                            Ocher powder      55-63                  93  H  H CH.sub.3                                                                          CH.sub.3                                                                             H     CH.sub.2                                                                              3,5-Cl.sub.2                                                                          Brown glassy matter                                                                              unmeasurable           94  H  H CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.2                                                                              3-Cl   Brown glassy matter                                                                              unmeasurable           95  H  H CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.2                                                                              3-CF.sub.3                                                                            Brown syrupy matter                                                                              unmeasurable           96  H  H CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.2                                                                              3,4-Cl.sub.2                                                                          Light brownish glassy                                                                            unmeasurable           97  H  H CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.2                                                                              3,5-Cl.sub.2                                                                          Yellowish crystals                                                                               unmeasurable           98  H  H CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.2                                                                              4-F    Ocher solid matter                                                                               155-156                99  H  H CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.2                                                                              4-CF.sub.3                                                                            Milky white powder                                                                               218-220                100 H  H CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.2                                                                              4-CN   Pinkish powder    234-237                101 H  H CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.2                                                                              2,4,6-(CH.sub.3).sub.3                                                                White powder      228-235                102 H  H CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.2                                                                              2,3,4,5,6-F.sub.5                                                                     White powder      180-181                103 H  H CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.2                                                                              4-OC.sub.2 H.sub.5                                                                    Milky white powder                                                                               179-180                104 H  H CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.2                                                                              4-OCH.sub.3                                                                           White crystals    165-168                105 H  H CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.2                                                                              4-C.sub.2 H.sub.5                                                                     Milky white powder                                                                               205-212                106 H  H CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.2                                                                              4-NO.sub.2                                                                            Milky white powder                                                                               217-221                107 H  H CH.sub.3                                                                          CH.sub.3                                                                             C.sub.2 H.sub.5                                                                      CH.sub.2                                                                              3,4-Cl Milky white crystals                                                                             185-187                108 H  H CH.sub.3                                                                          CH.sub.3                                                                             C.sub.2 H.sub.5                                                                      CH.sub.2                                                                              3-CF.sub.3                                                                            Light brownish crystals                                                                          107-108                109 H  H CH.sub.3                                                                          CH.sub.3                                                                             n-C.sub.3 H.sub.7                                                                    CH.sub.2                                                                              3,4-Cl.sub.2                                                                          Milky white crystals                                                                             210-213                110 H  H CH.sub.3                                                                          CH.sub.3                                                                             i-C.sub.3 H.sub.7                                                                    CH.sub.2                                                                              3,4-Cl.sub.2                                                                          White crystals    235-240                111 H  H CH.sub.3                                                                          CH.sub.3                                                                             i-C.sub.3 H.sub.7                                                                    CH.sub.2                                                                              4-Cl   White crystals    222-223                112 H  H H  H     H                                                                                     ##STR43##                                                                            4-Cl   White crystals    208-209                113 H  H H  H     H                                                                                     ##STR44##                                                                            3-Cl   White crystals    160-162                114 H  H H  H     H                                                                                     ##STR45##                                                                            3,4-Cl.sub.2                                                                          White crystals    233-236                115 H  H H  H     H     (CH.sub.2).sub.2                                                                      4-Cl   Milky white crystals                                                                             193- 196               116 H  H H  H     CH.sub.3                                                                             (CH.sub.2).sub.2                                                                      H      Colorless powder  184-185                117 H  H H  H     CH.sub.3                                                                             (CH.sub.2).sub.2                                                                      4-Cl   Colorless powder  195-197                118 H  H H  H     CH.sub.3                                                                             (CH.sub.2).sub.2                                                                      4-CH.sub.3                                                                            Light yellow powder                                                                              197-198                119 H  H CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.3                                                                             (CH.sub.2).sub.2                                                                      H      Light yellow powder                                                                              142-143                120 H  H CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.3                                                                             (CH.sub.2).sub.2                                                                      4-Cl   Light yellow powder                                                                              193-195                121 H  H H  H     H                                                                                     ##STR46##                                                                            3-Cl   White powder      249-256                122 H  H H  H     H                                                                                     ##STR47##                                                                            2-Cl   White crystals    255-258                123 H  H H  H     H                                                                                     ##STR48##                                                                            4-Cl   White crystals    240-244                124 H  H H  H     H                                                                                     ##STR49##                                                                            2,4-Cl.sub.2                                                                          Milky white crystals                                                                             250-253                125 H  H H  H     CH.sub.3                                                                              ##STR50##                                                                            2-Cl   Milky white crystals                                                                             242-244                126 H  H CH.sub.3                                                                          CH.sub.3                                                                             H                                                                                     ##STR51##                                                                            2-Cl   White crystals    212-216                127 H  H CH.sub.3                                                                          CH.sub.3                                                                             H                                                                                     ##STR52##                                                                            4-Cl   Light yellowish flaky                                                                            170-172s               128 H  H CH.sub.3                                                                          CH.sub.3                                                                             H                                                                                     ##STR53##                                                                            2,4-Cl.sub.2                                                                          White crystals    240-246                129 H  H CH.sub.3                                                                          CH.sub.3                                                                             H                                                                                     ##STR54##                                                                            3-Cl   Milky white crystals                                                                             119-125                130 H  H CH.sub.3                                                                          CH.sub.3                                                                             CH.sub.3                                                                              ##STR55##                                                                            2-Cl   White crystals    255-257                131 H  H H  H                                                                                     ##STR56##                                                                            ##STR57##                                                                            4-Cl   White down-like crystals                                                                         215-220                132 H  H CH.sub.3                                                                          CH.sub.3                                                                              ##STR58##                                                                            ##STR59##                                                                            4-Cl   White down-like crystals                                                                         250-253                133 H  H H  H     H     CH.sub.2                                                                              3,4-Cl.sub.2                                                                          White down-like crystals                                                                         206-207                __________________________________________________________________________

Referential Example 3:

Dissolved in toluene were 2.5 g (0.02 mole) of m-chloroaniline and a catalytic amount of pyridine, followed by dropwise addition of 1.9 g (0.022 mole) of diketene at 50° C. After completion of the dropwise addition, the resultant mixture was heated under reflux for 3 hours. Under ice-cooling, ligroin was added, and precipitated crystals were collected by filtration and were then washed first with ligroin and then with hexane. The crystals were then dried under reduced pressure to obtain 3'-chloroacetoacetanilide.

Example 134: ##STR60##

(i) Dissolved in diethyl ether was 2.1 g (0.01 mole) of the 3'-chloroacetanilide obtained in Referential Example 3, followed by a dropwise addition of 1.5 g (0.011 mole) of sulfuryl chloride at -5° C. The resultant mixture was stirred at -10--5° C. for 30 minutes. The reaction mixture was poured into ice water, neutralized with sodium hydrogencarbonate and then extracted with toluene. The organic layer was dried and concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione. The mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, recrystallized from isopropanol, and then dried at 120° C. under reduced pressure for 3 hours. The crystals were then suspended in methyl ethyl ketone and heated under reflux for 20 hours. The reaction mixture was cooled, and the resultant precipitate was collected by filtration, washed with acetone and then dried under reduced pressure to obtain 2.6 g of 3'-chloro-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 134) [yield: 72.2%].

PMR ppm δ (DMSO-d₆): 1.53 (6H,s,6.6(CH₃)₂), 2.53 (3H,s,3--CH₃), 4.27 (2H,s,5--CH₂ --), 7.03-8.00 (4H,m,aromatic proton), 10.80 (1H,s,--NH--).

(ii) Dissolved in water was 1.8 g (0.005 mole) of the thus-obtained 3'-chloro-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride. While stirring the aqueous solution at room temperature, a 20% aqueous solution of potassium carbonate was added dropwise. The resultant precipitate was collected by filtration and then washed and purified with a great deal of water. The precipitate was then dried under reduced pressure to obtain 1.3 g of 3'-chloro-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide

(melting point: 172°-173° C.; milky white powder).

Example 135: ##STR61##

(i) Dissolved in diethyl ether was 2.1 g (0.01 mole) of 4'-chloroacetanilide obtained in the same manner as in Referential Example 3, followed by a dropwise addition of 1.5 g (0.011 mole) of sulfuryl chloride at -5° C. The resultant mixture was stirred at -10°--5° C. for 30 minutes. The reaction mixture was poured in ice water, neutralized with sodium hydrogencarbonate and then extracted with toluene. The organic layer was dried and concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,4-dimethylimidazolidine-2-thione. The mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, washed with acetone and then dried under reduced pressure to obtain 3.4 g of 4'-chloro-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 135) [yield: 94.4%].

Melting point: 264°-268° C.

(ii) Dissolved in water was 1.8 g (0.005 mole) of the thus-obtained 4'-chloro-3,6,6-trimethyl-5 6-dihydroimldazo[2,1-b]thiazole-2-carboxyanilide hydrochloride. While stirring the aqueous solution at room temperature, a 10% aqueous solution of caustic soda was added dropwise. The resultant precipitate was collected by filtration and then washed and purified with a great deal of water. The precipitate was then dried under reduced pressure to obtain 1.0 g of 4'-chloro-3,6,6-trimethyl-5,6-dihydroimidazo[2,1-b]-thiazole-2-carboxyanilide

(melting point: 235°-236° C.; white powder).

Example 136: ##STR62##

(i) Dissolved in carbon tetrachloride were 2.8 g (0.01 mole) of 2'-chloro-4'-trifluoromethylacetoacetanilide obtained in the same manner as in Referential Example 3 and 1.4 g (0.0 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant suspension was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrate.. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,4-dimethyl-imidazolidine-2-thione. The mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, recrystallized from isopropyl ether-ethanol and then dried at 120° C. under reduced pressure for 3 hours to obtain 2.5 g of 2'-chloro-4'-trifluoromethyl-3,6,6-trimethyl-5,6-dihydroimidazo-[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 136) [yield: 61.9%].

Melting point: 148°-150° C.

Example 137: ##STR63##

Dissolved in carbon tetrachloride were 4.3 g (0.01 mole) of 3',4'-diiodoacetoacetanilide obtained in the same manner as in Referential Example 3 and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant suspension was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrated. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.2 g (0.01 mole) of 4-methylimidazolidine-2-thione. The mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, washed with acetone and then dried under reduced pressure to obtain 4.8 g of 3',4'-diiodo-3,6-dimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 137) [yield: 85.7%].

Melting point: 278°-280° C.

Example 138: ##STR64##

Dissolved in carbon tetrachloride were 2.5 g (0.01 mole) of 3',4'-diiodoacetoacetanilide obtained in the same manner as in Referential Example 3 and 1.4 g (0.01 mole) of N-chlorosuccinimide, followed by an addition of a small amount of benzoyl peroxide. The resultant suspension was heated under reflux for 1 hour. The reaction mixture was washed with water, dried and then concentrate. The residue was dissolved in methyl ethyl ketone, followed by an addition of 1.3 g (0.01 mole) of 4,5-dimethylimidazolidine-2-thione. The mixture was heated under reflux for 3 hours. Precipitated crystals were collected by filtration, recrystallized from isopropyl ether-ethanol, and the dried at 120° C. under reduced pressure for 3 hours to obtain 2.5 g of 3',4'-dichloro-3,5,6-trimethyl-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxyanilide hydrochloride (Compound 138) [yield: 64.1%].

Melting point: 240°-245° C.

Examples 139-171:

The following compounds were obtained in the same manner as in Referential Example 3 and Examples 134-138.

    __________________________________________________________________________      ##STR65##                                                                     No. R.sub.1                                                                            R.sub.2                                                                            X.sub.n  Appearance   Melting point (°C.)                   __________________________________________________________________________     139 H   H   H        Yellowish powder                                                                            207-209                                      140 H   H   2-Cl     White powder 205-212                                      141 H   H   3-Cl     White powder 196-198                                      142 H   H   4-Cl     Yellowish powder                                                                            240-244                                      143 H   H   2,4-Cl.sub.2                                                                            White powder 245-253                                      144 H   H   3,4-Cl.sub.2                                                                            Yellowish powder                                                                            234-235                                      145 H   H   3,5-Cl.sub.2                                                                            Yellowish powder                                                                            255-259                                      146 H   H   3-Br     White powder 201-204                                      147 H   H   4-NO.sub.2                                                                              Light yellowish powder                                                                      255-258                                      148 H   H   3-I      White powder 203-204                                      149 H   H   4-I      White powder 270                                          150 H   H   2-CH.sub.3                                                                              White powder 241-246                                      151 H   H   4-CH.sub.3                                                                              Milky white powder                                                                          208-210                                      152 H   H   2-OCH.sub.3                                                                             White powder 245-253                                      153 H   H   4-OCH.sub.3                                                                             White powder 210-215                                      154 H   H   3-OC.sub.3 H.sub.7 -i                                                                   White powder 115-122                                      155 H   H   2-Cl, 4-CF.sub.3                                                                        White powder 138-142                                      156 H   H   3-Cl, 4-F                                                                               Gray powder  150-154                                      157 CH.sub.3                                                                           H   3,4-I.sub.2                                                                             Brown powder 214-215                                      158 CH.sub.3                                                                           H   4-Cl     White powder 259-264                                      159 CH.sub.3                                                                           H   2-Cl, 4-CF.sub.3                                                                        White flaky crystals                                                                        178-182                                      160 H   CH.sub.3                                                                           3,4-Cl.sub.2                                                                            Brown syrupy matter                                                                         128-136                                      161 H   CH.sub.3                                                                           2,4-Cl.sub.2                                                                            Light orange crystals                                                                       172-175                                      162 H   CH.sub.3                                                                           3,5-Cl.sub.2                                                                            Yellowish crystals                                                                          155-160                                      163 H   CH.sub.3                                                                           3,4-I.sub.2                                                                             Light brownish crystals                                                                     266-268                                      164 H   CH.sub.3                                                                           4-I      White crystals                                                                              220-225                                      165 H   CH.sub.3                                                                           3-Cl, 4-F                                                                               Gray powder  251-256                                      166 H   CH.sub.3                                                                           3,5-(CF.sub.3).sub.2                                                                    Gray powder  261-265                                      167 H   CH.sub.3                                                                           H        White crystals                                                                              240-245                                      168 H   CH.sub.3                                                                           4-Br     White crystals                                                                              255-261                                      169 H   CH.sub.3                                                                           2,5-(OCH.sub.3).sub.2                                                                   Milky white powder                                                                          245-247                                      170 H   CH.sub.3                                                                           2-OCH.sub.3, 5-OH                                                                       Yellowish brown powder                                                                      279-281                                      171 H   CH.sub.3                                                                           3-Cl, 4-OH                                                                              Brown powder 272-273                                      __________________________________________________________________________

Examples 172-174:

The following compounds were prepared in the same manner as in Referential Example 2 and Example 44.

Compound 172: ##STR66##

(m.p.: 140°-142° C.; white powder)

Compound 173: ##STR67##

(m.p.: 102°-105° C.; slightly brown powder)

Compound 174: ##STR68##

(m.p.: 171°-174° C.; slightly yellow powder)

Having now fully described the invention, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the invention as set forth herein. 

We claim:
 1. A 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative represented by the following general formula [I] ##STR69## wherein R₁, R₂, R₃ and R₄ are either the same or different and mean individually a hydrogen atom or lower alkyl group, Y denotes a group of the following formula: ##STR70## wherein R₅ means a lower alkyl group, X denotes a hydrogen or halogen atom or a trifluoromethyl, lower alkyl, lower alkoxy or nitro group, n stands for an integer of 0-5, and when n is greater than 1, Xs are either the same or different; ##STR71## wherein A means a lower alkylene group which may be branched, R₆ denotes a hydrogen atom or a lower alkyl or cycloalkyl group, and X and n have the same meaning as defined above; ##STR72## wherein R₇ means a hydrogen, chlorine, bromine or iodine atom or a lower alkyl, lower alkoxy or nitro group; or ##STR73## wherein R₈ means a halogen atom or a lower alkoxy or trifluoromethyl group and R₉ denotes a halogen atom or a hydroxyl, lower alkoxy or trifluoromethyl group), with a proviso that at least one of R₁, R₂, R₃ and R₄ is a methyl group when the group Y is ##STR74## or a salt thereof.
 2. A 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative as claimed in claim 1, wherein Y denotes a group of the following formula: ##STR75## wherein A means a lower alkylene group which may be branched, R₆ denotes a hydrogen atom or a lower alkyl or cycloalkyl group, and X and n have the same meaning as defined in claim
 1. 3. A 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamid derivative as claimed in claim 1, wherein either one of R₂ and R₄ is a hydrogen atom and the other is a methyl group; and Y denotes a group of the following formula: ##STR76## wherein R₇ means a hydrogen, chlorine, bromine or iodine atom or a lower alkyl, lower alkoxy or nitro group; or ##STR77## wherein R₈ means a halogen atom or a lower alkoxy or trifluoromethyl group and R₉ denotes a halogen atom or a hydroxy, lower alkoxy or trifluoromethyl group.
 4. A 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative as claimed in claim 1, wherein Y denotes a group of the following formula: ##STR78## wherein R₅ means a lower alkyl group, X denotes a hydrogen or halogen atom or a trifluoromethyl, lower alkyl, lower alkoxy or nitro group, n stands for an integer of 0-5, and when n is greater than 1, Xs are either the same or different.
 5. A 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative as claimed in claim 1, wherein R₂ means a hydrogen atom and Y denotes a group of the following formula: ##STR79## wherein m stands for an integer of 1-3, and R₆, X and n have the same meaning as defined in claim
 1. 6. A 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative as claimed in claim 1, wherein R₂ means a hydrogen atom, R₄ stands for a methyl group, and Y denotes a group of the following formula: ##STR80## wherein R₁₇ and R₁₈ may be either the same of different and mean individually a hydrogen or chlorine or iodine atom or a trifluoromethyl group, with a proviso that R₁₈ is other than a trifluoromethyl group when R₁₇ is a hydrogen atom.
 7. A 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative as claimed in claim 1, wherein R₁ and R₂ are both hydrogen atoms and Y denotes a group of the following formula: ##STR81## wherein R₅, X and n have the same meaning as defined in claim
 1. 8. A 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative as claimed in claim 1, wherein R₁, R₂, R₃ and R₄ mean individually a hydrogen atom and Y denotes a group of the following formula: ##STR82## wherein R₁₉ means a hydrogen or alkyl group having 1-3 carbon atoms, m stands for an integer of 1-3, and X and n have the same meaning as defined above.
 9. A 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative as claimed in claim 1, wherein R₁ and R₂ mean individually a hydrogen atom, R₃ and R₄ denote individually a methyl group, and Y is a group of the following formula: ##STR83## wherein R₁₉ means a hydrogen atom or . alkyl group having 1-3 carbon atoms, m stands for an integer of 1-3, and X and n have the same meaning as defined above.
 10. A 5,6-dihydroimidazo[2,1-b]thiazole-2-carboxamide derivative as claimed in claim 1, wherein R₁ and R₃ mean individually a methyl group, R₂ and R₄ denote individually a hydrogen atom, and Y is a group of the following formula: ##STR84## wherein R₁₉ means a hydrogen atom or alkyl group having 1-3 carbon atoms, m stands for an integer of 1-3, and X and n have the same meaning as defined above. 